Voltage-gated sodium channels are found in all excitable cells including muscle cells and nerve cells of the central nervous system and peripheral nervous system. These sodium channels are essential in the initiation and propagation of electrical signals in the nervous system. Therefore, the sodium channels are appropriate and their suitable function is essential for normal function of the nerves. Ultimately, aberrant Nav channels play a critical role in a variety of diseases such as epilepsy, arrhythmia, myotonia, ataxia, multiple sclerosis, irritable bowel syndrome, urinary incontinence, visceral pain, depression, and pain. Currently, ten Nav channels are reported in Human (Nav1.1˜1.9, Nax). Among them, four channels, Nav1.3, Nav1.7, Nav1.8, and Nav1.9, are known to be closely associated with the transmission of pain signals, and thus are recognized as important analgesic targets.
There are a total of ten types in the Nav channels found until now as summarized in Table 1 below. Among the ten channels, nine channels, Nav1.1˜Nav1.9, form channels. Among them, Nav1.3, Nav1.6, Nav1.7, Nav1.8, and Nav1.9 are expressed in DRG.
TABLE 1DistributionTTX IC-50TypeGenetissuenMIndicationNav1.1SCN1ACNS/PNS10pain, epilepsy,neurodegenerationNav1.2SCN2ACNS10neurodegeneration,epilepsyNav1.3SCN3ACNS15Pain, epilepsyNav1.4SCN4ASk. muscle25MyotoniaNav1.5SCN5AHeart2000ArrhythmiaNav1.6SCN8ACNS/PNS6Pain, movementdisorderNav1.7SCN9APNS25Pain, neuroendocrinedisorderNav1.8SCN10APNS50000PainNav1.9SCN11APNS1000Pain
In particular, Nav1.7 is known to be highly expressed mainly in DRG (dorsal root ganglia) and sympathetic ganglia. In DRG that are sensory ganglia, the Nav1.7 channel is expressed in A- or C-fiber neurons, but frequently distributed in small neurons having a deep connection with pains. In particular, 85% of DRG are present in cells defined as nociceptors. This fact indicates that Nav1.7 has a close connection with pains.
The fact that Nav1.7 channel has a close connection with pains is well demonstrated in the results of not only animal experiments, but also human disease experiments. The results of animal experiments indicated that, when inflammation occurs, the gene transcript of Nav1.7 significantly increases and the expression of proteins also increases. This increase in transcript is believed to be attributable to an increase in NGF. The increased expression of Nav1.7 is believed to be the direct cause of an increase in excitability of sensory cells. In particular, when the gene of the Nav1.7 channels is removed or reduced, inflammatory pains are greatly reduced. However, animal experiments do not indicate that the removal or reduction of the Nav1.7 channel gene reduces neuropathic pains. However, there are many evidences that Nav1.7 is involved in a neuropathic pain in humans.
Assay results for family lineage that feel severe pain or no pain give many answers to pain studies. In particular, these results directly indicate that Nav1.7 plays an important role in causing pains. Genetically, there are two types of diseases which cause severe pain. In the case of erythromelalgia (or erythermalgia) among these diseases, severe pain is sometimes felt for a few hours when the body is slightly warm or takes exercises. At this time, the skin may become red, and the hand, the foot or the face may swell. The results of genetic research indicated that SCN9A (the human gene name of Nav1.7) is present at chromosomal sites that are associated with diseases. Nine mutations of Nav1.7 were found until now. These mutations lower activation threshold or result in slow deactivation of the channel. Therefore, these mutations can easily generate action potential even upon depolarization of some neurons [see, Dib-Hajj, S D. et al., TrendsinNeurosci., 30, 555-563:(2007)].
In the case of paroxysmal extreme pain disorder (PEPD) that is another inherited disease, pain is felt through life and caused when the bowels are evacuated or the anal region is stimulated. In addition to pain, the leg becomes red. As is known in the art, in PEPD, eight mutations occur in Nav1.7. These mutations occur mainly in sites which cause inactivation. The Nav channel has an inactivation ball in the linker between domains III and IV, and a peptide receiving region in the linker between the S5 and S6 segments of domains III and IV. Interestingly, mutations that cause PEPD all occur in these two regions. It appears that these cause a problem in the inactivation of Nav1.7. As expected, these mutations cause a problem in the inactivation of Nav1.7, resulting in slow deactivation of the channels (see, Fertleman, C. R. et al., Neuron, 52, 767-774: (2006)]. Therefore, the amount of electric current that enters through the channels increases.
Still another inherited disease is congenital indifference to pain (CIP). This disease results from mutation of the Nav1.7 channel and is present in Pakistani and Chinese family lineages. Patients suffering from this disease feel no pain [see, Cox, J. J, et al., Nature, 444, 894-898 (2006)]. CIP causes the loss of function of the Nav1.7 channel. Particularly, a mutation in this channel inhibits the expression of this channel. Thus, this channel is not expressed (see, Cox, J. J. et al., Nature, 444, 894-898 (2006)]. Interestingly, the knock-out of Nav1.7 does not influence other sensations, but it influences the olfactory sensation. This fact directly indicates that Nav1.7 does not overlap with other channels in pain transmission and the function thereof is not compensated for by other Nav channels.
As shown above for the above diseases, when a mutation in the Nav1.7 channels causes a gain of function, severe pain is felt, and when it causes a loss of function, labor pain is felt. This is a good clinical example that directly shows that the Nav1.7 channel is the major cause of pain. Therefore, it is considered that an antagonist that inhibits this channel will naturally lead to a potent analgesic effect.
However, if the Nav1.7 channel antagonist inhibits a plurality of Nav channels including the Nav1.7 channel, it can show adverse effects of various CNS disturbances, such as blurring of vision, dizziness, vomiting and sedation. In particular, if it inhibits the Nav1.5 channel, it can lead to cardiac arrhythmia and heart failure, which threaten life. For these reasons, selective inhibition of the Nav1.7 channels is very important.
Pains can be largely classified into three types: acute pain, inflammatory pain, and neuropathic pain. Acute pain performs an important protective function of maintaining the safety of organisms from stimuli that may cause tissue damage. Therefore, this pain is usually temporary and intense. On the other hand, inflammatory pain can be longer lasting, and the intensity thereof further rapidly increases. Inflammatory pain is mediated by various substances that are released during inflammation, including substance P, histamine, acid, prostaglandin, bradykinin, CGRP, cytokines, ATP, and other substances. The third pain is neuropathic and includes a nerve injury or a nerve injury caused by viral infection. It causes reorganization of circuits with neuronal proteins to cause pathological “sensitization”, which may result in chronic pain that is lasting for several years. This type of pain does not provide an advantage of adaptability and is particularly difficult to treat by current therapy.
In particular, neuropathic pain and incurable pain are great medical problems that have not been solved. Several hundred million patients are suffering from severe pain that is not well inhibited by current therapeutic methods. Drugs that are currently used for the treatment of pain include NSAIDS, COX-2 inhibitors, opioids, tricyclic antidepressants and anti-convulsions. Neuropathic pain is particularly difficult to treat, because it does not well respond to opioids until a high dose is reached. Currently, gabapentin is most widely used as a therapeutic agent against neuropathic pain, but it is effective for only 60% of the patients and is not greatly effective. This drug is generally safe, but is problematic in terms of sedative action at high doses.
Accordingly, studies on the discovery of a new regulator of the Nav1.7 channel and the use thereof for the treatment of acute pain, chronic pain, inflammatory pain and neuropathic pain have been actively conducted by many pharmaceutical companies including global pharmaceutical companies such as Merck, AstraZeneca (see, US2010-0197655; US2012-0010183; WO2013-086229; WO2013-177224; US2012-0238579; WO2007-145922).
Accordingly, the present inventors have conducted extensive studies to develop new compounds, and as a result, have found that compounds having chemical structures different from those of sodium channel blockers reported to date have excellent sodium channel blocking effects, thereby completing the present invention. In particular, the compounds of the present invention exhibit a higher affinity against Nav1.7 channels than the affinity against Nav1.5 channels. Advantageously, the compounds of the present invention do not exhibit little or no affinity against the Nav1.5 channels. Compounds falling within the scope of the present invention mainly have sodium channel inhibitory activity, but it is not excluded that products produced by a special in vivo environment or a metabolic process after adsorption of the compounds in vivo is likely to act as agonists and exhibit effective pharmacological activity.